Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes

Abraham Shaked; Bao Li Loza; Elisabet Van Loon; Kim M. Olthoff; Weihua Guan; Pamala A. Jacobson; Andrew Zhu; Claire E. Fishman; Hui Gao; William S. Oetting; Ajay K. Israni; Giuliano Testa; James Trotter; Goran Klintmalm; Maarten Naesens; Sumeet K. Asrani; Brendan J. Keating

doi:10.1038/s41591-022-01758-7

Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes

Abraham Shaked, Bao Li Loza, Elisabet Van Loon, Kim M. Olthoff, Weihua Guan, Pamala A. Jacobson, Andrew Zhu, Claire E. Fishman, Hui Gao, William S. Oetting, Ajay K. Israni, Giuliano Testa, James Trotter, Goran Klintmalm, Maarten Naesens, Sumeet K. Asrani, Brendan J. Keating

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Abstract

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1–71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8–65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07–5.00) (P = 1.92 × 10⁻⁷) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

Original language	English (US)
Pages (from-to)	999-1005
Number of pages	7
Journal	Nature Medicine
Volume	28
Issue number	5
DOIs	https://doi.org/10.1038/s41591-022-01758-7
State	Published - May 2022

Bibliographical note

Funding Information:
Funding for this study was received from the Fred and Suzanne Biesecker Pediatric Liver Center at Children’s Hospital of Philadelphia (A.S.), Gift-of-Life Organ Procurement Organization (A.S.), and National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) grant no. U01AI152960-01 (A.S. and B.J.K.).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Shaked, A., Loza, B. L., Van Loon, E., Olthoff, K. M., Guan, W., Jacobson, P. A., Zhu, A., Fishman, C. E., Gao, H., Oetting, W. S., Israni, A. K., Testa, G., Trotter, J., Klintmalm, G., Naesens, M., Asrani, S. K., & Keating, B. J. (2022). Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes. Nature Medicine, 28(5), 999-1005. https://doi.org/10.1038/s41591-022-01758-7

Shaked, A, Loza, BL, Van Loon, E, Olthoff, KM, Guan, W , Jacobson, PA, Zhu, A, Fishman, CE, Gao, H, Oetting, WS, Israni, AK, Testa, G, Trotter, J, Klintmalm, G, Naesens, M, Asrani, SK & Keating, BJ 2022, 'Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes', Nature Medicine, vol. 28, no. 5, pp. 999-1005. https://doi.org/10.1038/s41591-022-01758-7

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title = "Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes",

abstract = "Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1–71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8–65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07–5.00) (P = 1.92 × 10−7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.",

author = "Abraham Shaked and Loza, {Bao Li} and {Van Loon}, Elisabet and Olthoff, {Kim M.} and Weihua Guan and Jacobson, {Pamala A.} and Andrew Zhu and Fishman, {Claire E.} and Hui Gao and Oetting, {William S.} and Israni, {Ajay K.} and Giuliano Testa and James Trotter and Goran Klintmalm and Maarten Naesens and Asrani, {Sumeet K.} and Keating, {Brendan J.}",

note = "Funding Information: Funding for this study was received from the Fred and Suzanne Biesecker Pediatric Liver Center at Children{\textquoteright}s Hospital of Philadelphia (A.S.), Gift-of-Life Organ Procurement Organization (A.S.), and National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) grant no. U01AI152960-01 (A.S. and B.J.K.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Shaked, Abraham

AU - Loza, Bao Li

AU - Van Loon, Elisabet

AU - Olthoff, Kim M.

AU - Guan, Weihua

AU - Jacobson, Pamala A.

AU - Zhu, Andrew

AU - Fishman, Claire E.

AU - Gao, Hui

AU - Oetting, William S.

AU - Israni, Ajay K.

AU - Testa, Giuliano

AU - Trotter, James

AU - Klintmalm, Goran

AU - Naesens, Maarten

AU - Asrani, Sumeet K.

AU - Keating, Brendan J.

N1 - Funding Information: Funding for this study was received from the Fred and Suzanne Biesecker Pediatric Liver Center at Children’s Hospital of Philadelphia (A.S.), Gift-of-Life Organ Procurement Organization (A.S.), and National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) grant no. U01AI152960-01 (A.S. and B.J.K.). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/5

Y1 - 2022/5

N2 - Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1–71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8–65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07–5.00) (P = 1.92 × 10−7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

AB - Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1–71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8–65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07–5.00) (P = 1.92 × 10−7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

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Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes

Abstract

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